Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. One theory of schizophrenia suggests that it is due to an imbalance of dopamine tn certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of pro longed depression and apathy similar to the negative symptoms seen in schizophrenic patients. Similarly, the repeated administration of high doses of cocaine in rats can produce a decrease in locomotor activity and a lack of the usual sensitization state seen with lower dose stimulant drug challenges. In earlier studies, we evaluated the effects of cocaine administration on the uptake of dopamine in three brain areas of the rat. Cocaine (10 mg/kg) was administered intraperitoneally twice a day for seven days. The animals were sacrificed two weeks after the last injection and the up take of 3H-dopamine into synaptosomes from the frontal cortex, striatum and nucleus accumbens were examined. Control animals consisted of rats injected on the same schedule with saline. Animals receiving cocaine exhibited a significant decrease in locomotor activity as compared to the saline treated rats. In addition, the locomotor responses of these animals to a challenge dose of cocaine (2.5 and 5.0 mg/kg) or amphetamine (1 mg/kg) were the same, indicating a lack of behavioral sensitization. The up take of 3H-dopamine into synaptosomes of the frontal cortex of cocaine treated rats was significantly decreased (30%) as compared to the saline treated rats and was due to a decrease in the Vmax of the up take pump for dopamine. GBR 12909, a selective inhibitor of dopamine up take, and cocaine were less effective at inhibiting dopamine up take in synaptosomes from the frontal cortex as compared to the striatum and nucleus accumbens. Similar studies have been performed on dopamine up take in the cell bodies of the rat brain (ventral tegmental area and substantia nigra). The administration of cocaine (10 mg/kg x 2 for seven days) produced no differences in the uptake of dopamine in slices from the striatum, ventral tegmental area or substantia nigra at one or six weeks after the last injection. The Km values for dopamine up take were similar in these three brain areas, whereas the Vmax value for dopamine uptake in the striatum was approximately eight-fold higher than the Vmax in the substantia nigra and ventral tegmental area.